CN1150175C

CN1150175C - Derivatives of 1,3,4-oxadiazolone

Info

Publication number: CN1150175C
Application number: CNB998024112A
Authority: CN
Inventors: P��ķ˹; P·赫瓦瓦萨姆; С; 丁敏; J·E·小斯塔雷特
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 1998-01-29
Filing date: 1999-01-15
Publication date: 2004-05-19
Anticipated expiration: 2019-01-15
Also published as: ID26909A; LT2000068A; AU2230899A; LV12559B; KR20010077838A; CN1289249A; JP2002527352A; EE200000447A; AU735704B2; EP1051173A1; WO1999038510A1; TR200002019T2; LT4838B; EP1051173A4; HUP0102025A3; CO5090837A1; NZ505409A; SK10852000A3; LV12559A; TW550075B

Abstract

The present invention provides novel oxadiazolone derivatives having general formula (I), wherein A, B, D and R are as defined herein, or a nontoxic pharmaceutically acceptable salt or solvate thereof and are useful in the treatment of disorders which are responsive to the opening of the large conductance calcium-activated potassium channels.

Description

1,3,4-oxadiazole ketone derivatives

Invention field

The present invention relates to 1 of novelty; 3; the derivative of 4-oxadiazole-2 (3H)-ketone compound, this compound are that big electricity is led calcium activatory potassium (BK) channel modulators, therefore can be used for the protection of neuronal cell and lead the disease that dysfunction causes by cytolemma polarization and electricity.The present invention also provides the methods of treatment of using this novel substituted De oxadiazole ketone, and their pharmaceutical composition also is provided.

Background of invention

At US and European, apoplexy is considered to cause the invalid and dead the third-largest cause of disease of being grown up at present.In in the past 10 years, realize some methods of treatment that are used for reducing wind-induced brain injury, comprised AMPA/ kainic acid salt inhibitor, N-methyl-D-aspartate salt (NMDA) and adenosine reuptake inhibitor.The purpose of this invention is to provide the compound of novel adjusting potassium channel, particularly regulate big electricity and lead calcium activatory potassium (BK) passage, will can be used for reducing the neuronal damage in the local asphyxia state of apoplectic seizure.

Potassium channel plays key effect in the adjusting of the adjusting of cell membrane potential and cell excitement.Potassium channel originally experience adjusting [Cook, N.S. " pharmacology science trend " 9, the pp.21-28 (1988) of voltage, cellular metabolism, calcium ion and receptor-mediated process; Quast, U. and Cook, N.S. " pharmacology science trend " 10, pp.431-435 (1989)].Calcium activatory potassium (K _Ca) passage is a different set of ionic channel, they share the active dependency of calcium ion in the pair cell.K _CaThe activity of passage is subjected to [Ca in the cell ²⁺], the adjusting of membrane potential and phosphorylation.According to it at symmetrical K ⁺Single passage electricity in the solution is led K _CaPassage is divided into three subclasses: big electricity is led (BK)＞150pS; Middle electricity is led 50-150pS; Little electricity is led＜50pS (" pS " represents the electricity unit of leading, skin siemens (picosiemen)).Big electricity lead calcium activatory potassium (BK) passage be present in much can excited cell in, comprise neurone, myocardial cell and various types of smooth muscle cell [Singer, J.J. and Walsh, J.V. " Pfl ü gers Archiv. " 408, pp.98-111 (1987); Bar ó, I. and Escande, D. " Pfl ü gers Archiv. " 414 (supplementary issues 1), pp.S168-S170 (1989); Ahmed, F. etc. " Britain's pharmacology magazine " 83, pp.227-233 (1984)].

Potassium ion is on the resting membrane electric potential of control in most of excitable cells and keep the K of membrane potential near pact-90mV ⁺Equilibrium potential (E _k) on play decisive role.Have report to disclose, opening of potassium channel makes cell membrane potential to balance potassium membrane potential (E _k) close, cause the hyperpolarization [Cook, N.S. " pharmacology science trend " 9, pp.21-28 (1988)] of cell.The cell of hyperpolarization reduces the reactivity that potential deleterious depolarize stimulates.Both be subjected to voltage-regulation also to be subjected to Ca in the cell ²⁺The BK passage of regulating plays the effect that restriction depolarize and calcium enter, and particularly can effectively block destructive stimulus.Therefore, make the cell hyperpolarization, can protect the neuronal cell under the local asphyxia state by opening the BK passage.

S.Trivedi etc. are in " biological chemistry and biophysical studies communication " (1995), and 213, No.2 has discussed the effect of potassium channel in the human bladder smooth muscle movement among the pp.404-409.

Reported that some have the compound that BK opens active synthetic and natural origin.Utilize the lipid two-layer process, the oat pyrone that extracts from oat-common oat has been that a kind of BK passage is opened agent (International Patent Application WO is open on May 13rd, 93/08800,1993) by evaluation.Utilize outside medicine to paste, exist Xenopus laevisFind in the Medullated nerve fibre that the flavanoid Phloretin can influence Ca ²⁺The opening of activatory potassium channel [Koh, D-S. etc. " neuroscience wall bulletin " 165, pp.167-170 (1994)].

The United States Patent (USP) 3,971,803 of awarding to S.Rosenberger and K.Schwarzenbach on July 27th, 1976 relates to formula (i) compound:

Wherein

R ₁Be alkyl, cycloalkyl or aralkyl;

R ₂Be hydrogen or R ₁

R ₃Be hydrogen or C _1-4Alkyl;

Y and Z are O or S independently;

R ₄(1) if m=1 is C so _1-8Alkylidene group ,-C _xH _2x-Q-C _yH _2y-(Q is O or S, and x and y are integers, and sum of the two is 2 to 4), phenylene, diphenylene or naphthalene or

Group;

Perhaps (2) are if m=2 is alkylidene group, alkylene ether, alkylidene group thioether, diphenylene or naphthalene so.This compound is the antioxidant of organic polymer.

On March 24th, 1993, disclosed EPO 0-533276-A1 related to (ii) compound of formula:

Wherein one of P or Q are the phenyl that the ortho position replaces, and another is the benzyl that replaces.Formula (ii) compound is miticide and sterilant.

A.E.Wilder Smith discloses the formula (iii) preparation and the research of compound at " Arzneim.Forsch. " (1967) 67, No.17 among the pp.768-772:

Wherein X is H or Cl, and n is 1 or 2.This compound has the character that suppresses tubercule bacillus.Formula (iii) compound is not included in the replacement of hydroxyl contraposition.

J.L.Romine etc. have described a series of formulas phenylbenzene heterocycle (iv) in the disclosed International Patent Application WO 98/04135 on February 5th, 1998:

Wherein Het is a heterocyclic moiety, especially Xuan Zi oxadiazole ketone.This compound can be used as big electricity and leads calcium activatory potassium channel modulating agents, has wherein also described the raw material of preparation The compounds of this invention, and wherein Het is 1,3,4-oxadiazole-2 (3H)-ketone, m=1, n=O, R ^cBe chlorine, R ^dBe trifluoromethyl, R ^a=R ^b=R ^eBe hydrogen.

Compounds of the present invention is not all instructed or pointed out to these reference.

Summary of the invention

The invention provides 1,3 of novelty, 4-oxadiazole ketone derivatives has following formula:

Wherein A, B, D and R be as giving a definition,

Or its nontoxic pharmacy acceptable salt or solvate.The present invention also provides the pharmaceutical composition that comprises described derivative, also provide and treated the method for potassium channel being opened the illness of active sensitivity, for example local asphyxia, apoplexy, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury, sexual dysfunction and the urinary incontinence.

Detailed description of the invention

The invention provides 3-[(5-chloro-2-hydroxy phenyl) methyl]-5-[4-(trifluoromethyl) phenyl]-1,3, the novel derivative of 4-oxadiazole-2 (3H)-ketone, described ketone are that a kind of effectively big electricity is led calcium activatory K ⁺Passage (BK passage) is opened agent, and this novel derivatives has following formula:

Wherein

A be a direct key or-CH ₂O-;

B is a direct key or oxygen;

D is-(CH ₂) _n-or-CH ₂CHOHCH ₂-;

N is 1 to 4 integer;

R is-NR ¹R ²Or

Wherein It is the phase pair anion; And

R ¹, R ²And R ³Be hydrogen or C independently of one another _1-4Alkyl;

Or its nontoxic pharmacy acceptable salt or solvate.

The present invention also provides the treatment or the prevention method of Mammals illness, this illness is to lead the mediation that is opened for of calcium activatory K+ passage (BK passage) with big electricity, and this method comprises the treatment formula I compound of significant quantity or its nontoxic pharmacy acceptable salt described Mammals administration.Preferably, formula I compound can be used for treating local asphyxia, apoplexy, epilepsy, convulsions, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury, sexual dysfunction, the urinary incontinence and other illnesss to BK passage activating activities sensitivity.

Here and terminology in claims " C _1-4Alkyl " (unless indication is arranged in the context in addition) refer to straight or branched alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl.Preferably, these groups contain 1 to 2 carbon atom.

Here be intended to comprise and mineral acid and the formed nontoxic acid salt of organic acid and pair anion mutually with terminology in claims " nontoxic pharmacy acceptable salt " and " pair anion mutually ".The phase pair anion of hydrochlorate that is fit to and/or suitable acid is intended to comprise inorganic acid salt, for example hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt etc., pair anion mutually with organic acid salt and/or acid, for example formate, acetate, maleate, Citrate trianion, succinate, ascorbate salt, lactic acid salt, fumarate, mesylate and tartrate, they have been used for forming the salt of basic amine and tertiary amine.

Because The compounds of this invention may have unsymmetrical carbon, therefore the invention is intended to comprise racemoid and here with each enantiomeric forms of the I of formula described in claims compound, (D), (L) of carnitine and carnitine and (DL) type for example fall.

In general, pharmacy acceptable salt of the present invention is that wherein phase pair anion does not significantly participate in those of the toxicity of salt or pharmacologically active.In some cases, they have the required physical properties of pharmaceutical preparation, for example solubleness, no hygroscopicity, the compressibility relevant with forming tablet and with the consistency of other compositions that may use for the pharmacy purpose.Salt prepares with ordinary method: formula I compound is mixed with selected acid, preferably utilize a kind of excessive inert solvent commonly used and they are contacted in solution, solvent is water, ether, diox, methylene dichloride, Virahol, methyl alcohol, ethanol, ethyl acetate and acetonitrile for example.Salt also can prepare by metathesis, perhaps spent ion exchange resin is handled under certain condition, the suitable ion of the salt of its Chinese style I material is by another kind of ion exchange, be reflected under the isolating condition that to carry out desired substance and carry out, precipitation or use solvent extraction from solution for example, perhaps wash-out or be retained on the resin from the ion exchange resin.

Some The compounds of this invention that comprises its pharmacy acceptable salt can exist with the form of solvation, comprises the form of hydration, for example monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate etc.Product can be real solvate, and in other cases, product can only keep accidental solvent, or solvate adds the mixture of certain accidental solvent.Those skilled in the art should understand like this, and solvate forms is equivalent to the not form of solvation, also contains within the scope of the invention.

In the method for the invention, term " treatment significant quantity " refers to that the total amount of every kind of active ingredient of composition is enough to bring significant benefit to the patient, promptly cures with big electricity and leads calcium activatory K ⁺Passage is opened agent to be the acute state of feature or to improve its curative ratio.When being applicable to individually dosed independent activeconstituents, this term refers to this independent composition.When being applicable to when combination, this term refers to each the activeconstituents total amount that produces result of treatment, and with whether unite, continuously or administration simultaneously irrelevant.Here and terminology in claims " treatment " refer to that prevention or improvement and cytolemma polarization lead dysfunction diseases associated, tissue injury and/or symptom with electricity.

On the other hand, the invention provides the 3-[(5-chloro-2-hydroxy phenyl described in the WO 98/04135) methyl]-5-[4-(trifluoromethyl) phenyl]-1,3, the water-soluble prodrug of 4-oxadiazole-2 (3H)-ketone.The terminology used here prodrug is represented a kind of derivative of active medicine, and it transforms back active medicine after administration.Or rather, it refers to 1,3, the derivative of 4-oxadiazole-2 (3H)-ketone compound, and they can be active medicines and/or can carry out the hydrolysis of ester moiety or inferior methoxyl group ester moiety or the cracking of ester, thereby discharge active free drug.Hydrolyzable group serves as prodrug on the physiology, obtains parent drug itself by hydrolysis in vivo, and therefore, water-soluble prodrug of the present invention is that the administration institute of parent drug is preferred.

On the other hand, the invention provides the methods of treatment or the prevention method of Mammals illness, this illness is to lead calcium activatory K with big electricity ⁺Passage (BK passage) be opened for mediation, this method comprises the formula I compound of treatment significant quantity or its nontoxic pharmacy acceptable salt, solvate or hydrate described Mammals administration.Preferably, formula I compound can be used for treating local asphyxia, apoplexy, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury and the urinary incontinence, also can be used for treating male sexual disorder (erection problem by the blood flow that increases sexual organ, especially cavernous body, for example cause by diabetes, Spinal injury, radical cure prostatectomy, the spirituality cause of disease or any other reason) and Female sexual dysfunction, and other are to the illness of BK passage activating activities sensitivity.Most preferably, formula I compound can be used for the treatment of cerebral ischemia/apoplexy.

On the other hand, the invention provides pharmaceutical composition, it comprises at least a formula I compound bound drug auxiliary agent, carrier or thinner.

Formula I compound can be prepared by different operating, those of being set forth in embodiment, reaction process and the change example thereof for example, and they are apparent to those skilled in the art.The prodrug compound of various formula I can advantageously be prepared from formula II active drug substance, the latter itself is prepared by the general operation described in WO 98/04135 and the embodiment 1, is used as raw material in the method that they are set forth in reaction process 1 to 5.

Reaction process 1

Reaction process 1 has been set forth 1,3 of formula V, the preparation of 4-oxadiazole-2-(3H)-ketone derivatives.Formula II compound is handled in toluene with the phase transfer reagent (for example zephiran chloride triphenyl phosphonium) of phosgene and catalytic amount, and in sealing heating in vitro, obtain the chloro-formic ester of formula III, then with the N that suitably replaces, N-dialkyl amido alcohol is handled in inert organic solvents (for example methylene dichloride), obtains the carbonate products of formula IV.When needs preparation formula V compound, the aminocompound of formula IV is carried out quaternized with methylating reagent (for example methyl mesylate), obtain the quaternary amine of formula V by standard operation well known to those skilled in the art.

Reaction process 2

When needs when to prepare n wherein be 1 to 4 formula VIII compound; formula II compound is carried out deprotonation with alkali (for example sodium hydride); use required N then; N-dialkyl amido acyl chlorides carries out acidylate; obtain the ester of formula VII; it is quaternized advantageously to use alkylating reagent (for example methyl mesylate) to carry out it, obtains the quaternary amine of formula VIII.

Reaction process 3

Reaction process 3 has been set forth the preparation of formula XII compound, wherein R ¹, R ², R ³The same with the n definition.Formula II compound is carried out deprotonation with alkali (for example sodium hydride), carry out alkylation with chloromethyl methyl thioether then, obtain the sulphomethyl methyl ether of formula IX.Formula IX compound is handled with chlorizating agent (for example SULPHURYL CHLORIDE), obtained the monochloromethyl-ether of formula X, use required N then, the acid of N-dialkyl amido is handled in the presence of alkali (for example cesium carbonate), obtains the methoxyl group ester of corresponding formula XI.When needs preparation formula XII compound, the amine of formula XI is carried out quaternized with methylating reagent (for example methyl mesylate), obtain the quaternary amine of formula XII.

Reaction process 4

The preparation of formula XIII compound is easy to carry out, method is that the monochloromethyl-ether of formula X is handled in the presence of alkali (for example cesium carbonate) with carnitine, then products therefrom is handled with methylating reagent (for example methyl mesylate), obtained the quaternary amine of formula XIII.

Reaction process 5

Reaction process 5 has been set forth the preparation of formula XVII compound, wherein R ¹, R ², R ³The same with the n definition.Formula II compound is carried out deprotonation with alkali (for example sodium hydride), use butyl thiocarbonic acid SOH iodomethyl ester (iodomethyl butyl carbononothioate) to carry out alkylation then, obtain the methoxyl group thiocarbonic ester of formula XIV.Formula XIV intermediate is handled with chlorizating agent (for example SULPHURYL CHLORIDE), obtained the chloro-formic ester of formula XV, use required N then, N-dialkyl amido alcohol is handled, and obtains the methoxyl group carbonic ether of corresponding formula XVI.Formula XVI compound can be carried out alkylation with methylating reagent (for example methyl mesylate) subsequently, obtain the quaternary amine of formula XVII.

In the preferred a kind of embodiment of the present invention, formula I compound has formula Ia structure:

Wherein A be a direct key or-CH ₂O-; B is a direct key or oxygen; D is-(CH ₂) _n-or-CH ₂CHOHCH ₂-, wherein n is 1 to 4; And R ¹And R ²Be hydrogen or C _1-4Alkyl; Or its nontoxic pharmacy acceptable salt or solvate.More preferably, A be a direct key or-CH ₂O-; B is a direct key; D is-(CH ₂) _n-, wherein n is 1,2 or 3; And R ¹And R ₂Be methyl or ethyl.Most preferably, A is-CH ₂O-; B is a direct key; D is-(CH ₂) _n-, wherein n is 2 or 3; And R ¹And R ²It is methyl; Or its nontoxic pharmacy acceptable salt or solvate.

In the preferred another kind of embodiment of the present invention, formula I compound has formula Ib structure:

Wherein A be a direct key or-CH ₂O-; B is a direct key or oxygen; D is-(CH ₂) _n-or-CH ₂CHOHCH ₂-, wherein n is 1 to 4; R ¹, R ²And R ³Be hydrogen or C _1-4Alkyl;

It is the phase pair anion; Or its nontoxic pharmacy acceptable salt or solvate.More preferably, A be a direct key or-CH ₂O-; B is a direct key; D is-(CH ₂) _n-, wherein n is 1,2 or 3; R ¹, R ²And R ³It is methyl;

Be chlorine, bromine, sulfate radical, phosphate radical or methanesulfonate.

Most preferably, A is-CH ₂O-; B is a direct key; D is-(CH ₂) _n-, wherein n is 3;

R ¹, R ²And R ³It is methyl; It is methanesulfonate; Or its nontoxic pharmacy acceptable salt or solvate.

In another embodiment, the present invention includes pharmaceutical composition, it comprises at least a formula I compound bound drug auxiliary agent, carrier or thinner.

In another embodiment, the present invention relates to the treatment or the prevention method of Mammals illness, this illness is replied having opened of potassium channel, and this method comprises the treatment formula I compound of significant quantity or its nontoxic pharmacy acceptable salt, solvate or hydrate described Mammals administration.

In another embodiment, the present invention relates to be used for the treatment of the method for Mammals local asphyxia, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury, male and female sexual dysfunction, the urinary incontinence, especially apoplexy, this method comprises the treatment formula I compound of significant quantity or its nontoxic pharmacy acceptable salt, solvate or hydrate described Mammals administration.

Biological activity

Potassium (K ⁺) passage is the different K of 26S Proteasome Structure and Function ⁺The selectivity channel protein, they are immanent in cell, this illustrates that they have vital role [Rudy, B. " neuroscience " 25, pp.729-749 (1988)] on some key cells functions of adjusting.As a class of extensive distribution, K ⁺The distribution of passage is because of each member or various types of and different [Gehlert, D.R. etc. " neuroscience " 52, the pp.191-205 (1993)] of this kind.In general, in the cell, particularly neurone and myocyte such can excited cell in K ⁺The activation of passage causes the cytolemma hyperpolarization, perhaps under the situation of depolarize cell, causes polarizing again.Except serving as endogenous membrane voltage pincers, K ⁺Passage can also be reacted to important cell incident, for example the change or the intracellular Ca2+ (Ca of ATP concentration in the cell ²⁺) change of concentration.K ⁺The central role of passage in regulating a large amount of cell functions makes them become the target [Cook, N.S., " potassium channel: structure, classification, function and treatment potentiality ", Ellis Horwood, Chinchester (1990)] of the particularly important of treatment research.One class K is arranged ⁺Passage, promptly big electricity is led Ca ²⁺Activatory K ⁺Passage (BK or BK passage) is subjected to Ca in transmembrane voltage, the cell ²⁺With the adjusting of various other factors, the phosphorylation state of channel protein [Latorre, R. etc. " physiology yearbook " 51, pp.385-399 (1989)] for example.Big and the single channel conductance of BK passage is (usually＞150pS) with to K ⁺High degree of specificity explanation, but a small amount of passage may produce profound influence to membrane conductance and cell excitability.In addition, along with Ca in the cell ²⁺Increase, the probability of opening also increases, this explanation BK passage has participated in Ca ²⁺The adjusting of dependency phenomenon, for example secretion and Muscle contraction [Asano, M. etc. " pharmacological evaluation and therapeutics magazine " 267, pp.1277-1285 (1993)].

The BK passage is opened agent and is brought into play their cytosis [McKay, M.C. etc. " neurophysiology magazine " 71, pp.1873-1882 (1994) by the probability of opening that increases these passages; Olesen, S.-P. " Exp.Opin.Invest.Drugs " 3, pp.1181-1188 (1994)].Increase opening of each BK passage and cause cytolemma, the particularly hyperpolarization of depolarize cell jointly, this remarkable increase of being led by the electricity of full cell BK mediation causes.

Estimating embodiment 1 compound under the voltage clamp condition opens the BK passage and increases the outside (K of full cell ⁺) ability of BK mediation electric current, method is to measure the ability to extrinsic current [Butler, A. etc. " science " 261, the pp.221-224 (1993) that their increase cloning mammal (mSlo or hSlo) the BK mediation of heterogenous expression in xenopus ovocytes; Dworetzky, S.I. etc. " research of molecule brain " 27, pp.189-193 (1994)].Used two kinds of BK constitute on the thing representative structure homologous protein much at one, and have confirmed to have identical pharmacological action in our test.For from natural (background, non-BK) separates the BK electric current in the electric current, use ultrahigh concentration (50nM) specific and effective BK channel blocking toxin iberiotoxin (IBTX) [Galvez, A. etc. " biology and The Chemicals " 265, pp.11083-11090 (1990)].To the Relative Contribution of extrinsic current, method is to deduct remaining electric current in the presence of IBTX (non-BK electric current) from the electric current that obtains under every other experiment condition (contrast, medicine and washing lotion) to mensuration BK channel current to always.Sure is compound does not influence non-BK in the ovocyte under experimental concentration natural electric current.Concentration is that embodiment 1 compound of 1 μ M shows at least 5 ovocytes, compares with the electric current of control group IBTX sensitivity, makes the BK electric current increase by 126%.Utilize standard two electrodes voltage clamp technology [Stuhmer, W. etc. " Enzymology method " 207, pp.319-339 (1992)] to finish record; The voltage clamp scheme is made up of the depolarize step that continues 500-750ms, the maintenance current potential in the 20mV step is-60mV extremely+140mV.Test medium (modification Barth solution) consist of (mM): NaCl (88), NaHCO ₃(2.4), KCl (1.0), HEPES (10), MgSO ₄(0.82), Ca (NO ₃) ₂(0.33), CaCl ₂(0.41); PH7.5.

The following rapid screening of carrying out is to measure the ability of prodrug hydrolysis and release medicine (embodiment 1 compound).The 1mg/ml stock solution of preparation prodrug in distilled water or acetonitrile or PEG-400.In this mensuration, use from the rat of fresh collection or the blood plasma of human blood.Stock solution add 10 μ l prodrugs under 37 ℃ in 1ml blood plasma mixes lightly.Take out 100 μ l blood plasma after the mixing immediately, with 300 μ l acetonitrile cancellation (zero-time sample).Same collection sample, cancellation immediately in the time of 30 minutes.The sample of cancellation is centrifugal, obtains clarifying supernatant liquor, for the usefulness of analysis.Stock solution, T=0 and T=30 sample are analyzed with the HPLC assay method, isolate medicine from prodrug.The relative peak area in these samples according to prodrug and medicine, with different prodrugs be accredited as soon, slow releasing agent neutralizes.For example, in this model, the concentration of embodiment 13 compounds with 1mg/ml is dissolved among the PEG-400, with 10ug/ml cultivation in fresh rat blood plasma, under 37 ℃.Cultivate back 5 minutes analytical solution, indication embodiment 13 compounds are to embodiment 1 conversion of compounds.

In order to measure the ability of The compounds of this invention minimizing by loss cell due to the neurone ischemic, bring out standard focus cerebral ischemia by the permanent occlusion of left middle cerebral artery (MCA) and common carotid artery (CCA), the right CCA of Wistar rat was blocked one hour.Utilize " cerebral blood flow and metabolism magazines " 1 such as A.Tamura, [the K.Osborne etc. " neuroscience, neurosurgery and psychiatry magazine " 50 of method and improvement thereof under the temporo of pp.53-60 (1981), " neurosurgery " 31 such as pp.402-410 (1987) and S.Menzies, pp.100-107 (1992)] undergo surgery.

Estimate embodiment 13 compounds in the focus apoplexy model, this model relates to Wistar rat left side MCA and the permanent occlusion (MCAO and CCAO) of CCA and the temporary obstruction of right CCA.This operation causes the new cutis plate of reliable large volume infraction, and the latter utilizes behind the MCAO 24 hours to measure by the serial section that does not contain vital dye of brain.In this test, compound was passed through i.v. or i.p. administration in back two hours at obstruction.For example in this model, mesencephalic arteries block back two hours with embodiment 13 compounds by intravenously with single bolus administration (1mg/kg), compare remarkable about 17% the cortex infarct volume that reduced with (water) control group of vehicle treated.

Above-mentioned external and in vivo test result proves, 1 of novelty of the present invention, 3,4-oxadiazole-2 (3H)-ketone compound can be used for leading people's treatment of conditions that dysfunction causes by cytolemma polarization and electricity, preferably is applicable to local asphyxia, apoplexy, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury, sexual dysfunction, the urinary incontinence and other treatment of conditions to BK passage activating activities sensitivity.Most preferably, formula I compound can be used for the treatment of cerebral ischemia/apoplexy.

Formula I compound or its pharmaceutical composition can be used for illness or other treatment of conditions, alleviation or eliminations relevant with the BK passage.Such illness comprises that local asphyxia, apoplexy, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury, sexual dysfunction, the urinary incontinence and other open the illness of agent sensitivity to potassium channel.

When being used for the treatment of, the pharmaceutically active compounds of formula I carries out administration as pharmaceutical composition usually, The latter standard and common process comprise at least a this compound as the activeconstituents of necessity one of (or), and solid or the pharmaceutically acceptable carrier of liquid and optional pharmaceutically acceptable auxiliary agent and vehicle.

Pharmaceutical composition comprises the formulation that is applicable to oral, parenteral (comprising subcutaneous, intramuscular, intracutaneous and intravenously), segmental bronchus or nasal administration.Therefore, if used solid carrier, preparation can be pressed into tablet, put into the form of hard capsule or lozenge or lozenge with powder or particulate form so.Solid carrier can contain conventional vehicle, for example tamanori, weighting agent, compressing tablet lubricant, disintegrating agent, wetting agent etc.If necessary, tablet can be used the common process dressing.If used liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injection with the form of the suspension of vehicle, moisture or non-water so, or desciccate, prepares again with water or other suitable carriers before use.Liquid preparation can contain conventional additive, for example suspension agent, emulsifying agent, wetting agent, nonaqueous carrier (comprising edible oil), sanitas and correctives and/or tinting material.Concerning parenteral admin, carrier comprises sterilized water usually, and major part is at least, but also can use salt brine solution, glucose solution etc.Also injectable suspension can be used, conventional suspension agent can be used in this case.Can also in parenteral dosage form, add conventional sanitas, buffer reagent etc.Useful especially is directly with the parenteral formulation administration with formula I compound.Pharmaceutical composition prepares according to common process, and these technologies are suitable for containing an amount of activeconstituents, promptly according to the required preparation of formula I compound of the present invention.For example referring to " Lei Mingdun pharmaceutical science " Mack publishing company, Easton, PA, the 17th edition, 1985.

The dosage that formula I compound reaches result of treatment will not only depend on factors such as patient age, body weight and sex and administering mode, and depend on the degree of required potassium channel activating activities and the used specific compound effect at specified disease.Certainly, the treatment of specific compound and dosage can be with the unit dosage administrations, and therefore unit dosage will be adjusted by those skilled in the art, with reflection relative reactivity level.Decision about used given dose (with the administration number of times of every day) is under doctor's guidance, can change dosage adapting to particular case of the present invention by volumetry, thereby reach required result of treatment.

Formula I compound or its pharmaceutical composition in activeconstituents, are about 0.1ng/kg to 10mg/kg body weight to the suitable dose suffering from the Mammals that maybe may suffer from any disease as herein described, comprise the people.Concerning parenteral admin, dosage can be in the scope of 0.1ng/kg to 1.0mg/kg body weight, and this is an intravenous administration.Activeconstituents is successive administration preferably, perhaps divides one to four time to wait dosed administration in one day.But, give low dose usually, increase dosage gradually, up to the optimal dose of determining under the treatment condition the host.

But self-evidently be, the actual dosage of compound will determine according to relevant environment by the doctor, comprise the disease of being treated, in order to selection, selected route of administration, age, body weight and the reaction of individual patient and the seriousness of patient's symptom of the compound of administration.

Provide the following example to illustrate mode, and never be interpreted as restriction, because a lot of examples that become of invention all are possible in the implication of invention invention.

The explanation of embodiment

In the following example, all temperature are degree centigrade to provide.Fusing point writes down on the Gallenkamp capillary melting point apparatus, and temperature is not calibrated.Proton resonance ( ¹H NMR) on Bruker AC300, writes down.All spectrum shown in measure in the solvent, chemical shift be with downward bias from δ unit's report of interior mark tetramethylsilane (TMS), coupling constant is reported with hertz (Hz) in the proton.Divisional mode is expressed as follows: s is unimodal, and d is bimodal, t triplet, q quartet, m multiplet, br broad peak, bimodal bimodal of dd, wide bimodal of bd, dt triplet bimodal, wide unimodal of bs, dq quartet bimodal.Use infrared (IR) spectrum of Potassium Bromide (KBr) on PerkinElmer 781 spectrophotometers, to measure measurement range 4000cm ^-1To 400cm ^-1, the 1601cm of p-poly-phenyl vinyl film ^-1Absorption is proofreaied and correct, with reciprocal centimetre (cm ^-1) report.Low Resolution Mass Spectra (MS) and apparent molecular weight (MH ⁺) or (M-H) ^-On Finnigen TSQ 7000, measure.High resolution mass spectrum is measured with the FAB pattern at Kratos MS50, and uses cesium iodide/glycerine as confidential reference items.Ultimate analysis is with reported in weight percent.

The following example is set forth the preparation manipulation of raw material, intermediate and according to the preparation method of product of the present invention.Also should it is evident that for a person skilled in the art, the embodiment that will be set forth below the suitable replacement of raw material disclosed herein and method will obtain, they are also contained within the scope of the present invention.

Embodiment 1

3-[(5-chloro-2-hydroxy phenyl) methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-Evil two Azoles-2 (3H)-ketone

Steps A: 5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone

At N ₂Down, with 4-(trifluoromethyl) phenylformic acid hydrazides (commercial can obtaining) from MaybridgeChemicals (5g, 24.5mmol) be dissolved in THF (250ml)/triethylamine (2.7ml, 26mmol), add 1,1 '-carbonyl dimidazoles (4.2g, 26mmol).Solution stirred 18 hours down at 24 ℃, concentrated, and resistates is dissolved in ethyl acetate, with 1N HCl solution, saturated NaHCO ₃Solution and salt water washing, dry then (MgSO ₄).Concentrate, obtain 5g (89%) title compound, with sample recrystallization from diethyl ether/hexane:

mp?214-216℃.MS?m/z.231(MH ⁺).

IR(KBr)3280，1778，1608，1420，1318，1170，1114cm ^-1；

¹H?NMR(DMSO-d ₆)δ7.87(2H，d，J＝8.3Hz)，7.96(2H，d，J＝8.3Hz)，12.77(1H，br.s)；

Analytical calculation value: C ₉H ₅F ₃N ₂O ₂064H ₂O:C, 46.74; H, 2.24; N, 12.11.

Measured value: C, 47.07; H, 2.10; N, 12.34.

Step B: 3-[(5-chloro-2-p-methoxy-phenyl) methyl]-5-[4-(trifluoromethyl) benzene Base]-1,3,4-oxadiazole-2 (3H)-ketone

Under nitrogen, to CH ₃Add 5-[4-(trifluoromethyl) phenyl among the CN (300ml)]-1,3,4-oxadiazole-2 (H)-ketone (11.75g, 51mmol) with 5-chloro-2-methoxy-benzyl bromine [N.Meanwell etc. " biological organic and medical chemistry wall bulletin " 6, pp.1641-1646 (1996)] (12.0g, 51mmol) and 11.2g (81mmol) salt of wormwood, add potassiumiodide (0.2g, 1.2mmol).Solution refluxed 16 hours, and vigorous stirring is poured in the water (1500ml) in cooling into.Filtering-depositing obtains a solid, from CH ₃Recrystallization among the CN obtains 15.2g (78%) title compound.

mp?144-145℃.MS(ESI)m/z：385(MH ⁺).

IR(KBr)3440，1782，1492，1324，1248，1168.cm ^-1；

¹H?NMR(300MHz，DMSO)δ3.79(3H，s)，4.91(2H，s)，7.07(1H，d，J＝8.8Hz)，7.35-7.38(2H，m)，7.88(2H，d，J＝8.4Hz)，7.96(2H，d，J＝8.2Hz)；

Analytical calculation value: C ₁₇H ₁₂ClF ₃N ₂O ₃0.1H ₂O:C, 52.81; H, 3.19; N, 7.25.

Measured value: C, 53.03; H, 3.20; N, 7.31.

Step C: 3-[(5-chloro-2-hydroxy phenyl) methyl]-5-[4-(trifluoromethyl) benzene Base]-1,3,4-oxadiazole-2 (3H)-ketone

With 3-[(5-chloro-2-p-methoxy-phenyl) methyl]-5-[4-(trifluoromethyl) phenyl]-1,3, (15.2g, 39.6mmol) (19.7g 0.17mol) mixes 4-oxadiazole-2 (3H)-ketone, heats 2 hours down at 225 ℃ with pyridine hydrochloride.The solution of heat is poured among the 800ml 1N HCl, and mixture stirred 10 minutes.Collect solid, dry under 80 ℃ of vacuum with 1N HCl washing, obtain the 13.1g pale solid.Recrystallization from acetonitrile obtains the 10.8g title compound, is loose spicule, mp 217-218 ℃ of .MS m/z:371 (MH ⁺).

IR(KBr)3354，1762，1500，1324，1068cm ^-1；

¹H?NMR(DMSO-d ₆)δ4.98(2H，s)，6.84(1H，d，J＝8.7?Hz)，7.20(1H，dd，J＝8.7Hz，2.6Hz)，7.30(1H，d，J＝2.5Hz)，7.89(2H，d，J＝8.6Hz)，7.97(1H，d，J＝8.6?Hz)，10.11(1H，br.s)；

Analytical calculation value: C ₁₆H ₁₀ClF ₃N ₂O ₃: C, 51.84; H, 2.72; N, 7.56.

Measured value: C, 51.88; H, 2.58; N, 7.57.

Embodiment 2

3-[[5-chloro-2-[[[[2-(dimethylamino) ethyl] oxygen] carbonyl] oxygen] phenyl] first Base]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone

Steps A: 4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] Phenyl Chloroformate 99

In sealing in vitro, with 3-[(5-chloro-2-hydroxy phenyl) methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone (1g, 2.69mmol) and BnPh ₃The suspension of PCl (25mg) in 1.9 moles of toluene solutions of phosgene (15ml) is while stirring 120 ℃ of following heated overnight.After removing excess phosgene, the toluene solution rotary evaporation to doing, is obtained the chloro-formic ester product, be white semi-solid (1.18g).

Step B: 3-[[5-chloro-2-[[[[2-(dimethylamino) ethyl] oxygen] carbonyl] oxygen] phenyl] first Base]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone

While the chloro-formic ester (0.6g, anhydrous CH 0.15mmol) that stir to steps A ₂Cl ₂(5ml) drip in cold (0 ℃) solution pure 2-(dimethylamino) ethanol (0.41g, 0.45mmol).Make the gained mixture temperature rise to room temperature, kept 2-3 hour.With CH ₂Cl ₂At room temperature rotary evaporation makes resistates at ether and 5%NaHCO ₃Between distribute.Separate the ether layer, use the salt water washing, dry then (MgSO ₄).Evaporating solvent obtains product, is light yellow oil (0.613g).Crude product and anhydrous HCl are reacted in ether, obtain 3-[[5-chloro-2-[[[[2-(dimethylamino) ethyl] oxygen] carbonyl] oxygen] phenyl] methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (the 3H)-corresponding hydrochloride of ketone.

mp?160-163℃；MS?m/z?486(MH ⁺).

Embodiment 3

2-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] oxygen] ethyl] the trimethyl ammonium methanesulfonates

With thick 3-[[5-chloro-2-[[[[2-(dimethylamino) ethyl] oxygen] carbonyl] oxygen] phenyl] methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone is dissolved among 1: 1 ether-EtOAc, adds pure methyl mesylate (2eqt.).Mixture at room temperature stirs and spends the night.Filter the solid that collecting precipitation comes out, dry in a vacuum then with the ether washing, obtain title compound, be white solid:

mp?190-195℃(dec.)；

IR(KBr，cm ^-1)1193，1318，1765，1777；

¹H?NMR(CDCl ₃)δ2.76(s，3H)，3.51(s，9H)，4.19(m，2H)，4.75(m，2H)，4.89(s，2H)，7.17(d，J＝8.6Hz，1H)，7.25(s，1H)，7.38(dd，J＝8.6?and2.5Hz，1H)，7.54(d，J＝2.5Hz，1H)，7.71(d，J＝8.4Hz，1H)，7.91(d，J＝8.1Hz，1H)；MS?m/z?500(M ⁺).

The general operation of the preparation of embodiment 4-11

The general operation that is used for preparation formula VIIa-c and VIIIa-c compound is described below, and this is also described in reaction process 2.The preparation method of formula VIa-c acyl chlorides makes the DMF of corresponding acid and oxalyl chloride and catalytic amount at CH ₂Cl ₂Middle reaction.Isolate the HCl salt of formula VIa-c acyl chlorides, need not during use to be further purified.Add corresponding formula VI acyl chlorides (1.2eqt.) while stirring in embodiment 1 compound (1eqt.) and the suspension of NaH (2eqt.) in anhydrous diethyl ether, mixture stirred 3-4 hour.Reaction mixture is used 5%NaHCO with ether and EtOAc dilution ₃, water, salt water washing, dry then (MgSO ₄).With the solvent rotary evaporation, make resistates recrystallization from ether-hexane, obtain formula VIIa-c compound.Add pure methyl mesylate in 1: the 1 ether-EtOAc solution of formula VIIa-c compound, mixture at room temperature stirs and spends the night.The white solid that filtering-depositing comes out, dry in a vacuum then with the ether washing, obtain corresponding pure formula VIIIa-c compound.

Embodiment 4

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole -3-yl] methyl] phenyl (dimethylamino) acetic ester(VIIa, n=1)

mp?112-113℃；MS?m/z：456(MH ⁺).

Analytical calculation value: C ₂₀H ₁₇ClF ₃N ₃O ₄: C, 52.70; H, 3.76; N, 9.22.

Measured value: C, 52.51; H, 3.66; N, 9.10.

Embodiment 5

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole -3-yl] methyl] phenyl-3-(diethylin) propionic ester(VIIb, n=2)

mp?179-181℃；MS?m/z：498(MH ⁺).

Analytical calculation value: C ₂₃H ₂₃ClF ₃N ₃O ₄HCl:C, 51.70; H, 4.53; N, 7.86.

Measured value: C, 51.46; H, 4.67; N, 7.71.

Embodiment 6

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole -3-yl] methyl] phenyl-4-(dimethylamino) butyric ester(VIIc, n=3)

mp162-164℃；

Analytical calculation value: C ₂₂H ₂₁ClF ₃N ₃O ₄HCl:C, 50.78; H, 4.26; N, 8.08.

Measured value: C, 49.51; H, 4.35; N, 7.80.

Embodiment 7

[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-Evil Diazole-3-yl] methyl] phenoxy group] carbonyl] methyl] the trimethyl ammonium methanesulfonates(VIIIa, n=1)

mp?230-232℃；MS?m/z：470(M ⁺).

Analytical calculation value: C ₂₁H ₂₀ClF ₃N ₃O ₄CH ₃SO ₃: C, 46.69; H, 4.10; N, 7.42.

Measured value: C, 46.06; H, 4.06; N, 7.21.

Embodiment 8

2-[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] ethyl] diethylmethyl ammonium methanesulfonates(VIIIb, n=2)

mp＞260℃

Embodiment 9

3-[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] propyl group] the trimethyl ammonium methanesulfonates(VIIIc, n=3)

mp＞260℃；MS?m/z：498(M ⁺).

Analytical calculation value: C ₂₃H ₂₄ClF ₃N ₃O ₄CH ₃SO ₃: C, 48.53; H, 4.58; N, 7.07.

Measured value: C, 48.61; H, 4.58; N, 7.03.

Embodiment 10

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole -3-yl] methyl] phenyl (methylamino-) acetic ester

mp?186-188℃(dec.).

Embodiment 11

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole -3-yl] methyl] phenyl-3-alanine ester

mp?184-185℃(dec.).

Embodiment 12

[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-Evil two Azoles-3-yl] methyl] phenoxy group] methyl-4-(dimethylamino) butyric ester(XTc, n=3)

Steps A: 3-[[5-chloro-2-(methyl sulfo-methoxyl group) phenyl] methyl]-5-[4-(fluoroform Base) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone (IX)

Under nitrogen, while stirring to sodium hydride (0.77g, 60% mineral oil dispersed system, 19.4mmol) drip 3-[(5-chloro-2-hydroxy phenyl in the suspension in HMPA (15ml)) methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone (6.0g, anhydrous HMPA (50ml) solution 16.2mmol).The gained yellow solution stirred 30 minutes, drip then pure chloromethyl methyl thioether (1.49ml, 17.8mmol).Reaction mixture at room temperature stirs and spends the night, and product extracts with ethyl acetate (500ml).The saturated NaHCO of EtOAc layer ₃, water, salt water washing, dry then (MgSO ₄).With the EtOAc rotary evaporation, obtain yellow semisolid, recrystallization from ethyl acetate/hexane obtains title compound, is white crystal (4.4g, 70%).

¹H?NMR(CDCl ₃)δ2.28(s，3H)，5.00(s，2H)，5.22(s，2H)，6.92(d，J＝8.5Hz，1H)，7.3(m，2H)，7.74(d，J＝8.4Hz，2H)，7.96(d，J＝8.3Hz，2H).

IR(KBr，cm ^-1)：1779，1608，1494，1328，1238，1176，1126.

Analytical calculation value: C ₁₈H ₁₄ClF ₃N ₂O ₃S:C, 50.18; H, 3.28; N, 6.50.

Measured value: C, 50.19; H, 3.32; N, 6.52.

Step B: 3-[[5-chloro-2-(chlorine methoxyl group) phenyl] methyl]-5-[4-(trifluoromethyl) benzene Base]-1,3,4-oxadiazole-2 (3H)-ketone(X)

Under nitrogen, while stir to steps A compound (3.5g, CH 8.12mmol) ₂Cl ₂(40ml) drip in the solution pure SULPHURYL CHLORIDE (0.78ml, 9.75mmol).Reaction mixture at room temperature stirred 4 hours.The TLC Indicator Reaction is complete.Rotary evaporation is removed excess reagent and CH ₂Cl ₂After, product is dry under vacuum, obtains title compound, is pale solid (3.4g, 100%).

MS?m/z：419(MH ⁺).

¹H?NMR(CDCl ₃)δ5.0(s，2H)，5，94(s，2H)，7.18(d，J＝9.2Hz，1H)，7.38(m，2H)，7.74(d，J＝8.4Hz，2H)，7.96(d，J＝8.3Hz，2H).

IR(KBr，cm ^-1)：1773，1611，1572，1487，1325，1163，1128.

Analytical calculation value: C ₁₇H ₁₁Cl ₂F ₃N ₂O ₃0.25H ₂O:C, 48.19; H, 2.76; N, 6.61.

Measured value: C, 48.04; H, 2.68; N, 6.53.

Step C: [4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methyl-4-(dimethylamino) butyric ester(XIc, n=3)

While stirring to Cs ₂CO ₃(1.306g, 4.01mmol) with hydrochloric acid 4-(dimethylamino) butyrates acidifying thing (0.352g, 2.1mmol) add in the suspension in acetone (20ml) step B the chloromethane oxycompound (0.8g, 1.91mmol).Reaction mixture at room temperature stirs and spends the night.The TLC Indicator Reaction is complete.With the acetone rotary evaporation, add salt brine solution.Filter and collect yellow mercury oxide, wash with water, air-dry then.Thick solid recrystallization from ethyl acetate/hexane obtains title compound XIc, is white solid (0.64g, 65%).

mp?115-117℃；

¹H?NMR(DMSO-d ₆)δ1.49(m，2H)，2.02(t，J＝7.0Hz，2H)，2.25(t，J＝7.3Hz，2H)，3.32(s，6H)，4.92(s，2H)，5.79(s，2H)，7.24(d，J＝8.8Hz，1H)，7.43(dd，J＝2.6Hz，8.8Hz，1H)，7.50(d，J＝2.6Hz，1H)，7.90(d，J＝8.5Hz，2H)，7.98(d，J＝8.3Hz，2H).

IR(KBr，cm ^-1)：1776，1764，1607，1492，1416，1324，1121.

Analytical calculation value: C ₂₃H ₂₃ClF ₃N ₃O ₅0.5H ₂O:C, 52.83; H, 4.63; N, 8.04.

Measured value: C, 53.00; H, 4.70; N, 8.04.

Embodiment 13

3-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] propyl group] the trimethyl ammonium methylsulfonic acid Ester(XIIc, n=3)

With embodiment 12 compounds (XIc) (0.95g 1.85mmol) is dissolved in ethyl acetate (10ml), drip pure methyl mesylate (0.32ml, 3.7mmol).Reaction mixture at room temperature stirs and spends the night.Collect white precipitate, carry out purifying, obtain title compound, be white solid (0.95g, 82%) with the ether development.Recrystallization from ethanol/ether obtains white crystal:

mp?156-158℃；MS?m/z：528(MH ⁺).

¹H?NMR(DMSO-d ₆)δ1.91(m，2H)，2.27(s，3H)，2.43(t，J＝7.1Hz，2H)，3.01(s，9H)，3.22(m，2H)，4.91(s，2H)，5.81(s，2H)，7.24(d，J＝8.9Hz，1H)，7.43(dd，J＝2.7Hz，8.8Hz，1H)，7.49(d，J＝2.6Hz，1H)，7.90(d，J＝8.5Hz，2H)，7.98(d，J＝8.4Hz，2H)；

Analytical calculation value: C ₂₄H ₂₆ClF ₃N ₃O ₅CH ₃SO ₃: C, 48.12; H, 4.68; N, 6.73.

Measured value: C, 48.15; H, 4.74; N, 6.71.

Embodiment 14

[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-Evil Diazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] methyl] the trimethyl ammonium methanesulfonates(XIIa, n=1)

To embodiment 12 step B compounds Xs (0.4g, 0.95mmol), Cs ₂CO ₃(0.342g, 1.05mmol) and N, (0.108g adds acetone (20ml) to the N-N-methylsarcosine in mixture 1.05mmol).Reaction mixture at room temperature stirs and spends the night.With the acetone rotary evaporation, add salt solution then.Collect the white precipitate of compounds X Ia (n=1), it is dissolved in acetonitrile, add pure methyl mesylate (0.053ml).Reaction mixture at room temperature stirred 2 days.Evaporating solvent adds ether.Collecting precipitation, recrystallization carries out purifying from acetonitrile/ether, obtains title compound, is white solid (0.13g, 23% liang of step).mp：100-104℃.MS?m/z：500(M ⁺).

¹H?NMR(DMSO-d ₆)δ2.27(s，3H)，3.33(s，9H)，4.60(s，2H)，5.09(s，2H)，5.48(s，2H)，7.24(d，J＝8.9Hz，1H)，7.52(dd，J＝2.6Hz，8.8Hz，1H)，7.60(d，J＝2.6Hz，1H)，7.90(d，J＝8.6Hz，2H)，7.97(d，J＝8.3Hz，2H).

Analytical calculation value: C ₂₂H ₂₂ClF ₃N ₃O ₅CH ₃SO ₃1.5H ₂O:

C，44.34；H，4.53；N，6.74.

Measured value: C, 44.35; H, 4.28; N, 6.46.

Embodiment 15

Hydrochloric acid [4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methyl-3-(diethylin) propionic ester(XIb, n=2)

To embodiment 12 step B compounds Xs (0.4g, 0.95mmol), Cs ₂CO ₃(0.622g, 1.91mmol) (0.108g adds acetone (20ml) in mixture 1.05mmol) with hydrochloric acid 3-(diethylin) propionic acid.Reaction mixture at room temperature stirred 3 days.With the acetone rotary evaporation, in resistates, add salt solution.The white solid that collecting precipitation comes out (0.38g, 75%).(0.16g, (0.36ml 0.36mmol), at room temperature kept 3 hours the diethyl ether solution of adding 1N HCl in ethyl acetate solution 0.30mmol) to crude product while stirring.Filter the hydrochloride (0.11g, 64%) of collecting title compound XIb:

mp?165-167℃(dec.)；MS?m/z：528(MH ⁺).

¹H?NMR(DMSO-d ₆)δ1.16(t，J＝7.2Hz，6H)，2.93(t，J＝7.8Hz，2H)，3.01-3.10(m，4H)，3.19-3.25(m，2H)，4.93(s，2H)，5.84(s，2H)，7.27(d，J＝8.8Hz，1H)，7.44(dd，J＝2.6Hz，8.8Hz，1H)，7.51(d，J＝2.6Hz，1H)，7.91(d，J＝8.5Hz，2H)，8.00(d，J＝8.3Hz，2H)，10.5(s，br，1H).

Analytical calculation value: C ₂₄H ₂₅ClF ₃N ₃O ₅HCl:C, 51.08; H, 4.64; N, 7.45.

Measured value: C, 46.94; H, 4.42; N, 6.76.

Embodiment 16

3-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl]-the 2-hydroxypropyl] trimethylammonium The ammonium methanesulfonates(XIII)

While stir to embodiment 12 step B compounds Xs (0.4g, 0.95mmol) and Cs ₂CO ₃(0.342g 1.05mmol) adds (L)-fall carnitine [Colucci, W.J. in the suspension in acetone (20ml); Turnbull, Jr., S.P.; Gandour, R.D. " analytical biochemistry " 162, pp.459-462 (1987)] (0.155g, 1.05mmol).Reaction mixture at room temperature stirred 2 hours.With the acetone rotary evaporation, add entry, use extracted with diethyl ether then.Extraction liquid is water, salt water washing then, dry (MgSO ₄).The evaporation ether obtains light yellow spumescence solid, then it is dissolved in ether, adds the 0.1ml methyl mesylate.Reaction mixture at room temperature stirs and spends the night.The solid that collecting precipitation comes out with the ethylacetate/ether development, obtains title compound, is pale solid (0.2g, 33% liang of step).

mp：98-101℃.MS?m/z：544(M ⁺).

¹H?NMR(DMSO-d ₆)δ2.30(s，3H)，2.52-2.58(m，2H)，3.10(s，9H)，3.34-3.41(m，2H)，4.43(m，1H)，4.94(s，2H)，5.73(d，J＝6.2Hz，1H)，5.81(d.J＝5.5Hz，1H)，5.84(d，J＝6.6Hz，1H)，7.27(d，J＝8.8Hz，1H)，7.44(dd，J＝2.7Hz，8.8Hz，1H)，7.49(d，J＝2.6Hz，1H)，7.91(d，J＝8.5Hz，2H)，7.99(d，J＝8.3Hz，2H)；

IR(KBr，cm ^-1)：3307，1784，1751，1490，1417，1324，1194，1123，1065.

Analytical calculation value: C ₂₄H ₂₆ClF ₃N ₃O ₆CH ₃SO ₃0.75H ₂O:

C，45.95；H，4.70；N，6.43.

Measured value: C, 45.88; H, 4.69; N, 6.13.

Embodiment 17

2-[[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] oxygen] ethyl] the trimethyl ammonium first Sulphonate(XVIIa, n=1)

Steps A: The 3-[[2-[[[(butylthio) carbonyl] oxygen] methoxyl group]-the 5-chloro-phenyl-] first Base]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone(XIV)

Under nitrogen, (1.11g, (60%, in the mineral oil, 144mg 3.6mmol), makes temperature rise to room temperature then to add sodium hydride in anhydrous HMPA (6ml) 3mmol) cold (0 ℃) solution to formula II compound while stir.After 30 minutes, the gained yellow solution is cooled to 0 ℃, drips pure O-iodo-methyl-S-butyl thiocarbonic ester (O-iodomethyl-S-butylcarbonothioate) [Folkman then, M. and Lund, F. " synthesize " pp.1159, (1990)] (1.0g, 3.6mmol).Make the gained mixture temperature rise to room temperature, stirring is spent the night.In reaction mixture, add saturated brine, the white solid that filtering-depositing comes out, water thoroughly washs.Thick wet solid is dissolved in 1: 1: 1 EtOAc-CH ₂Cl ₂-THF, dry then (MgSO ₄).Filter, evaporating solvent obtains a white solid (1.76g), and recrystallization from ether obtains pure XIV (693mg, 62%).

Step B: [4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2, the 3-dihydro-2-oxo- -1,3,4-oxadiazole-3-yl] methyl] phenoxy group] the methyl chloride manthanoate(XV)

Under nitrogen, while stir to steps A compound (258mg, anhydrous CH 0.5mmol) ₂Cl ₂(2ml) add in the solution pure SULPHURYL CHLORIDE (80 μ l, 1mmol).The gained mixture at room temperature stirred 2 hours.At room temperature rotary evaporation is extremely dried with reaction mixture, remains on then under the high vacuum, obtains the chloro-formic ester of required formula XV, is white solid (0.23g).

Step C: 3-[[5-chloro-2-[[[[[2-(dimethylamino) ethyl] oxygen] carbonyl] oxygen] methoxyl group] Phenyl] methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone(XVIa, n=1)

While the anhydrous CH that stirs to the formula XV of step B compound (0.23g) ₂Cl ₂(5ml) add pure anhydrous 2-(dimethylamino) ethanol (134mg) in the solution, mixture stirs and spends the night.Reaction mixture CH ₂Cl ₂5%NaHCO is used in dilution then ₃Quencher.Separate organic layer, water, salt water washing, dry then (MgSO ₄).Evaporation CH ₂Cl ₂, obtain title compound, be light yellow oil (0.21g).

Step D: 2-[[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxygen Generation-1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] oxygen] ethyl] trimethyl ammonium Methanesulfonates(XVIIa, n=1)

Step C crude product (0.2g) is dissolved in 1: 1 ether-EtOAc (5ml), handles with methyl mesylate (2eqt.).Mixture at room temperature stirs and spends the night, and the white solid that filtering-depositing comes out is dry in a vacuum then with the ether washing, obtains title compound, is white solid (94mg):

mp?145-150℃(dec.)；

¹H?NMR(CDCl3)δ2.76(s，3H)，3.45(s，9H)，4.16(m，2H)，4.71(m，2H)，4.96(s，2H)，5.79(s，2H)，6.98(d，J＝8.4Hz，1H)，7.31-7.34(m，2H)，7.75(d，J＝8.4Hz，2H)，7.97(d，J＝8.2Hz，2H)；MS?m/z?530(M ⁺).

Claims

1, following formula: compound

Wherein

A be a direct key or-CH ₂O-;

B is a direct key or oxygen;

D is-(CH ₂) _n-or-CH ₂CHOHCH ₂-;

N is 1 to 4 integer;

R is-NR ¹R ²Or

Wherein It is the phase pair anion; And

R ¹, R ²And R ³Be hydrogen or C independently of one another _1-4Alkyl;

Or its nontoxic pharmacy acceptable salt or solvate.

2, the compound of claim 1, wherein A is a direct key, and B is a direct key, and D is-(CH ₂) _n-.

3, the compound of claim 2 is selected from:

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenyl (dimethylamino) acetic ester;

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenyl-3-(diethylin) propionic ester;

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenyl-4-(dimethylamino) butyric ester;

[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] methyl] the trimethyl ammonium methanesulfonates;

2-[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] ethyl] diethylmethyl ammonium methanesulfonates;

3-[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] propyl group] the trimethyl ammonium methanesulfonates;

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenyl (methylamino-) acetic ester; With

4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenyl-3-alanine ester;

Or its nontoxic pharmacy acceptable salt, phase pair anion or solvate.

4, the compound of claim 1, wherein A is a direct key, and B is an oxygen, and D is-(CH ₂) _n-.

5, the compound of claim 4 is selected from:

3-[[5-chloro-2-[[[[2-(dimethylamino) ethyl] oxygen] carbonyl] oxygen] phenyl] methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazole-2 (3H)-ketone; With

2-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] carbonyl] oxygen] ethyl] the trimethyl ammonium methanesulfonates;

Or its nontoxic pharmacy acceptable salt, phase pair anion or solvate.

6, the compound of claim 1, wherein A is-CH ₂O-, B are direct keys, and D is-(CH ₂) _n-.

7, the compound of claim 6 is selected from:

[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methyl-4-(dimethylamino) butyric ester;

3-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] propyl group] the trimethyl ammonium methanesulfonates;

[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] methyl] the trimethyl ammonium methanesulfonates; With

Hydrochloric acid [4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methyl-3-(diethylin) propionic ester;

Or its nontoxic pharmacy acceptable salt, phase pair anion or solvate.

8, the compound of claim 7, it is 3-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] propyl group] the trimethyl ammonium methanesulfonates.

9, the compound of claim 1, wherein A is-CH ₂O-, B are direct keys, and D is-CH ₂CHOHCH ₂-.

10, the compound of claim 9, it is 3-[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl]-the 2-hydroxypropyl] the trimethyl ammonium methanesulfonates.

11, the compound of claim 1, wherein A is-CH ₂O-, B are oxygen, and D is-(CH ₂) _n-.

12, the compound of claim 11, it is 2-[[[[[4-chloro-2-[[5-[4-(trifluoromethyl) phenyl]-2,3-dihydro-2-oxo--1,3,4-oxadiazole-3-yl] methyl] phenoxy group] methoxyl group] carbonyl] oxygen] ethyl] the trimethyl ammonium methanesulfonates.

13, be used for the treatment of big electricity is led the pharmaceutical composition that calcium activatory potassium channel is opened the illness of agent sensitivity, it comprises as the defined compound of claim 1, and pharmaceutically acceptable carrier or thinner.

14, the defined compound of claim 1 is used for the treatment of Mammals in preparation and big electricity is led calcium activatory potassium channel and open purposes in the medicine of responsive illness.

15, the purposes of claim 14, wherein said illness are local asphyxia, apoplexy, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, Spinal injury, sexual dysfunction and the urinary incontinence.

16, the purposes of claim 15, wherein said illness is an apoplexy.